Nucleosides, their analogues and derivatives are an important class of therapeutic agents. A number of nucleoside analogues such as 3′-azido-3′-deoxythymidine (AZT), 2′3′-dedeoxy-cytidine (DDC), 1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine, 5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine and 2-hydroxymethyl-4-(guanin-9′-yl)-1,3-dioxalane have shown antiviral activity against retroviruses such as human immunodeficiency virus, human B virus and human T-lymphotropic virus.
Emtricitabine also known as FTC, chemically designated as 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (Formula I), is a synthetic nucleoside analog having activity against human immunodeficiency virus type 1 (HIV-1) reverse transcriptase.

Emtriva® (Emtricitabine) is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. It contains two chiral centers and exists in the form of two pairs of optical isomers (i.e., two cis-configurations and two in the trans-configuration). However, cis (2R,5S) isomer exhibits higher biological activity as compared to its trans counterpart. Several stereoselective processes employing chiral auxiliaries have been developed to selectively obtain the cis (2R,5S) isomer.
WO 92/20669 provides a process for preparing cis nucleosides (including emtricitabine), involving condensation of L-menthyl cis-1,3-oxathiolan-5S-acetoxy-2R-carboxylate with 5-fluorocytosine in the presence of Lewis acid and reduction of L-menthyl 1,3-oxathiolan-5S-(5-fluorocytosin-1-yl)-2R-carboxylate (referred to as menthyl emtricitabine) so formed in a polar solvent. Owing to the high solubility of emtricitabine in polar solvents, its isolation from this medium poses practical problems and restricts the viability of this process on commercial scale.
WO 95/29174 provides a process for preparing cis nucleoside analogues in which L-menthyl cis-1,3-oxathiolan-5-yl-2R-carboxylate derivative is condensed with 5-fluorocytosine in the absence of Lewis acid to afford L-menthyl 1,3-oxathiolan-5S-(5-fluorocytosin-1-yl)-2R-carboxylate. It further provides a process for isolation of such nucleoside analogues in the form of salts. It specifically exemplifies the isolation of lamivudine, a defluoro analogue of emtricitabine as its salicylate. However, it has been found subsequently that the process gives desired results for lamivudine but is found to be completely inapplicable for emtricitabine. For example, WO 2004/085432 provides a process for isolating oxalate salt of L-menthyl 1,3-oxathiolan-5S-(5-fluorocytosin-1-yl)-2R-carboxylate which upon reduction gives emtricitabine free base in low yields.
WO 2009/084033 provides a process, which involves reducing L-menthyl 1,3-oxathiolan-5S-(5-fluorocytosin-1-yl)-2R-carboxylate and isolating emtricitabine as a salt which upon treatment with organic base gives emtricitabine free base in low yields.
Hence, the present inventors felt a need for developing a commercially viable stereoselective process for the preparation of emtricitabine which achieves high performance, high yield, with reduced complexity cost, by eliminating cumbersome chromatographic steps for purification.